Alkoxy-substituted indanes and the production thereof

ABSTRACT

The present invention relates to alkoxy-substituted indanes, their preparation and use and to the preparation and use of the corresponding alkoxy-substituted indanones.

The present invention relates to alkoxy-substituted indanes, theirpreparation and use and to the preparation and use of the correspondingalkoxy-substituted indanones.

1-indanones are important intermediates for the preparation ofpharmaceutical products (EP-A 421 759 and EP-A 404 536) and ofUV-filters (EP-A 823 418, DE-A 10055940.9-44).

The preparation of 1-indanones can be effected by oxidation ofcorrespondingly substituted indanes with oxidising agents such as, forexample, oxygen or air in the presence of metal catalysts such as, forexample, Co salts (J. prakt. Chem. 334, 373 (1992)).

This oxidation is described, for example, in EP-A 162 465 on the basisof trimethyl- and tetramethyl-indanes with the aid of chromiumacetoacetate and cobalt acetoacetate.

Furthermore, such oxidations are also possible with imides such as, forexample, N-hydroxy-phthalimide (J. Org. Chem. 60, 3934 (1995)).

The reaction of alkyl-substituted aromatic compounds such as, forexample, toluene or xylene (J. Org. Chem. 54, 1418 (1989)) with isopreneare (sic) described in the literature for the preparation of indanes.Phenols or cresols can be reacted analogously, as is described in DE-A 2603 835, although the yields are low.

Alkoxy-substituted indanes are covered in a broad general formula inEP-A 286 523 and EP-A 807 850, but neither alkoxy-substituted indanesnor the preparation thereof is explicitly described in thesepublications.

The aim was thus to find a suitable method of preparation foralkoxy-substituted indanes and alkoxy-substituted 1-indanones.

Surprisingly, it has been found that in the reaction with isoprene(2-methyl-1,3-butadiene) alkoxy-substituted aromatic compounds yieldconsiderably better yields than is the case with phenols or cresols.

The present invention relates to alkoxy-substituted indanes of theFormula (II)

where

-   R¹, R², R³ and R⁴—independently of one another—can be hydrogen,    C₁-C₈-alkyl or C₁-C₈-alkoxy, with the proviso that at least one of    these radicals is C₁-C₈-alkoxy.

Preferred alkoxy-substituted indanes according to the invention are:

where the substituents R—independently of one another—can denote methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, n-pentyl ori-pentyl.

Particularly preferred compounds are:

Very particularly preferred compounds are:

The present invention furthermore relates to the preparation ofcompounds of the Formula (II) from alkoxy-substituted aromatic compoundsof the Formula (I) and isoprene in the presence of an acid catalyst andto the use of the compounds of the Formula (II) for the preparation ofthe corresponding alkoxy-substituted 1-indanones (III).

The following reaction equation can illustrate the method according tothe invention for the preparation of the compounds of the Formula (II):

where

-   R¹, R², R³ and R⁴—independently of one another—can be hydrogen,    C₁-C₈-alkyl or C₁-C₈-alkoxy, with the proviso that at least one of    these radicals is C₁-C₈-alkoxy.

Preferred alkoxy-substituted aromatic compounds used according to theinvention are:

where the substituents R—independently of one another—can denote methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, n-pentyl ori-pentyl.

Particularly preferred alkoxy-substituted aromatic compounds are:

A very particularly preferred compound is:

The reaction of the alkoxy-substituted aromatic compounds (I) withisoprene takes place in the presence of acid catalysts. In general,customary Friedel-Crafts catalysts can be used. Acid catalysts that canbe used are, for example, inorganic acids, such as phosphoric acid orsulphuric acid, or organic acids such as methanesulphonic acid. Furthersuitable catalysts are Lewis acids, such as, for example, AlCl₃, ZnCl₂,FeCl₃, TiCl₄ and BF₃ adducts. The preferred catalyst is sulphuric acid;70-95% (m/m) sulphuric acid is particularly preferred.

The molar ratio between the alkoxy-substituted aromatic compounds (I)and isoprene is preferably between 7:1 and 1:2, particularlypreferentially between 3:1 and 1:1.

The weight-related ratio between the alkoxy-substituted aromaticcompounds (I) and sulphuric acid is preferably between 5:1 and 1:1,particularly preferentially between 3:1 and 2:1.

The reaction temperature is advantageously between 0 and 100° C.,preferably between 20 and 80° C. and particularly preferentially between30 and 50° C. The reaction time is advantageously between 10 and 300min, preferably between 30 and 120 min and particularly preferentiallybetween 40 and 90 min.

The present invention furthermore relates to the preparation ofalkoxy-substituted 1-indanones by oxidation of compounds of the Formula(II) and the use of novel alkoxy-substituted 1-indanones for thepreparation of pharmaceutical or agrochemical active compounds and forthe preparation of UV filters.

The following equation can illustrate the method for the preparation ofthe alkoxy-substituted 1-indanones of the Formula (III):

where

-   R¹ to R⁴ have the above mentioned meaning.

In general, this oxidation in the benzyl position can take place inaccordance with methods known from the literature.

The oxidation is preferably carried out with oxygen, it also beingpossible to dilute the oxygen with other gases. Dilution with inertgases is advantageous; oxidation with air is particularly advantageous.

The reaction can be carried out under elevated pressure. Typically, thereaction is carried out under pressures in the range of 1 to 50 bar abs.

This oxidation can be carried out in particular in the presence ofcompounds of the metals manganese, iron, cobalt, chromium, nickel orcopper. Halides, nitrates, sulphates, oxides, acetates or tungstenatesof the said metals are preferred. Furthermore, the said metals can beused in the form of complexes with chelate-forming agents such as, forexample, acetylacetonates, phthalocyanines, porphyrins, orazaporphyrins. The metal compounds can be used as such or also onsupports. Furthermore, the said catalysts can be used on their own or inmixtures.

Preferred metals are nickel, cobalt and copper. Preferred metalcompounds are the halides, sulphates, acetates and acetylacetonates.Particularly preferred metal compounds are Co(II) acetate, Co(II)acetylacetonate, Co(III) acetylacetonate, Ni(II) acetate and Ni(II)acetylacetonate.

The amount of metal compound used can be varied within wide ranges andis usually between 0.00001 and 15% (mol/mol), preferably 0.25 to 10%(mol/mol).

This oxidation can also be carried out in the presence ofN-hydroxy-imides. Preferred N-hydroxy-imides are N-hydroxy-succinimide,N-hydroxy-maleinimide and N-hydroxy-phthalimide; N-hydroxy-phthalimideis particularly preferred. The amount of N-hydroxy-imides used can bevaried within wide ranges and is usually between 0.001 and 15%(mol/mol), preferably 1 to 10% (mol/mol).

It is likewise advantageous to carry out the oxidation in the presenceof a compound of the above mentioned metals and a N-hydroxy-imide,preferably a Ni(II), Co(II) or Co(III) compound andN-hydroxy-phthalimide, Co(II) acetate, Co(II) acetyl-acetonate, Co(III)acetylacetonate, Ni(II) acetate and Ni(II) acetylacetonate beingpreferred.

The reaction temperatures are typically 0 to 200° C., preferably 20 to120° C., and particularly preferentially 30 to 90° C.

Depending on the consistency of educts or products, an organic diluentcan be used. Diluents that can be used are, for example, hydrocarbons,ethers, alcohols, alkyl- or aryl-nitriles as well as organic acids.Lower alcohols, such as, for example, methanol, ethanol or i-propanol,lower organic acids, such as, for example, acetic acid, as well asalkyl- or aryl-nitriles, such as, for example, acetonitrile orbenzonitrile, are particularly suitable.

Furthermore, the oxidation can be carried out under the conditions ofphase transfer catalysts by adding the abovementioned metal salts in theform of an aqueous solution to the alkoxy-substituted indanes, which areimmiscible with water, with the addition of a phase transfer catalyst.The alkoxy-substituted indanes can be used on their own or in a solventin this reaction.

Advantageously, the reaction can be carried out, for example, inbenzonitrile as organic phase and a solution of Co-(II) chloride,Cu-(II) nitrate and tetrabutylammonium bromide as aqueous phase.

The present invention furthermore relates to novel alkoxy-substituted1-indanones of the Formula (IV) and to their preparation by the methoddescribed above.

where

-   R¹, R² and R³ have the abovementioned meaning.

Preferred alkoxy-substituted 1-indanones are:

The following examples can illustrate the invention:

EXAMPLES Example 1 3,3,6-trimethyl-5-methoxy-indane and3,3,4-trimethyl-5-methoxy-indane

300 g sulphuric acid (85% (m/m)) are initially introduced, withstirring, and a mixture of 732 g o-cresyl methyl ether and 153 gisoprene is added in the course of 50 min. During this addition, thetemperature is kept to a maximum of 30° C. by cooling. The reactionmixture is stirred for a further 20 min at this temperature, 400 g wateris added, the phases are separated and washed with sodium bicarbonateuntil neutral. After distilling off the excess o-cresyl methyl ether,300 g of the mixture of isomers (ratio 3:1) is obtained, whichcorresponds to a yield of 70% of theory.

The two isomers are separated by distillation in a 1 m packed column andcan be used individually for the oxidation.

Example 2 3,3,6-trimethyl-5-butoxy-indane and3,3,4-trimethyl-5-butoxy-indane

The reaction is carried out analogously to Example 1, o-cresyl butylether being employed. The yield is 70% of theory.

Preparation of 2-methyl-butoxy-benzene (o-cresyl Butyl Ether)

540 g (5.0 mol) o-cresol, 500 g n-butanol and 560 g (5.0 mol) 50% (m/m)potassium hydroxide solution are initially introduced and heated underreflux, the water being removed azeotropically. 463 g (5.0 mol) n-butylchloride are then metered in under reflux in the course of 2 h, furtherwater being cycled out. After metering, the reaction mixture is stirredfor a further 2 h, cooled to 80° C., hydrolysed with 800 g water andadjusted to pH 4 with 50% (m/m) sulphuric acid. The phases are separatedat 70° C. After distillation, 794 g product with a purity of 94% isobtained.

Yield: 90% of theory.

Example 3 3,3,6-trimethyl-5-butoxy-indan-1-one

100 g 3,3,6-trimethyl-5-butoxy-indane are dissolved in 400 g acetic acidand 1 g Co-II acetate is added. The reaction mixture is heated to 40°C., with stirring, and oxygen is passed through this solution for 10hours. After cooling to room temperature, 500 g water and 500 g methyltert.-butyl ether are added. After phase separation, the organic phaseis rinsed with a further 200 g water and distilled in a 30 cm packedcolumn. 80 g 3,3,6-trimethyl-5-butoxy-indan-1-one is obtained, whichcorresponds to a yield of 75% of theory. The compound can berecrystallised from heptane and a white solid is obtained, meltingpoint: 59° C.

Example 4 3,3,4-trimethyl-5-butoxy-indan-1-one

The reaction is carried out analogously to Example 3,3,3,4-trimethyl-5-butoxy-indane being employed. The yield is 70% oftheory.

1. A method for the preparation of compounds having the formula

said method comprising reacting an alkoxy substituted aromatic compoundwith isoprene in the presence of an acid catalyst, wherein said alkoxylsubstituted aromatic compound has the formula:

wherein R is independently selected from the group consisting of methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl andi-pentyl.
 2. A method for the preparation of compounds of the formulas

wherein R is independently selected from the group consisting of methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl andi-pentyl, said method comprising the step of oxidizing a compound offormulas


3. The method according to claim 2, wherein the oxidation is carried outusing oxygen as an oxidizing agent.
 4. The method according to claim 3,wherein the oxidation is carried out in the presence of a metalcompound, where the metal is selected from the group consisting ofmanganese, iron, cobalt, chromium, nickel and copper.
 5. The methodaccording to claim 3, wherein the oxidation is carried out in thepresence of an N-hydroxy-imide.
 6. The method according to claim 3,wherein the oxidation is carried out with the aid of phase transfercatalysis.
 7. The method according to claim 4, wherein the oxidation iscarried out in the presence of an N-hydroxy-imide.
 8. The methodaccording to claim 2, wherein the oxidation is carried out with the aidof phase transfer catalysis.